A sub-study of the CORE64* trial casts doubt on the usefulness of Calcium Scoring (CS) in safely excluding significant Coronary Artery Disease (CAD), but in symptomatic individuals already selected for invasive Coronary Angiography.

After the publication of new guidelines on Chest pain of recent onset by the National Institute of Clinical Excellence (NICE)1 earlier this year formalised the role they feel CS should play in the assessment of chest pain and prompted us to recently perform an audit of our own practice at St. Georges Hospital, I thought it would be interesting to review an article published by Gottlieb et. al. earlier this year in the February 16th issue of the Journal of the American College of Cardiology (JACC), which raises a number of interesting and important points.2

This article, which was a sub-study of their previously published CORE64 trial,3, 4 caused controversy when it was published as it seemed to suggest that CS cannot be used to reliably exclude significant coronary artery disease or the need for revascularisation, and was interpreted by many as such. In addition, an editorial accompanying that article in the same issue debated the prognostic value of a zero calcium score in the light of these new findings.5 This debate was recently re-ignited by a number of letters to the editor of JACC regarding the study and its accompanying editorial, which were published in the August 10th, 2010 issue.

The CORE64 sub-study included 291 patients in total (73% male, average age 59). Of these patients, 5% had a low pre-test probability of obstructive CAD (derived using the method validated by Morise et al.),6 75% had an intermediate probability, and 20% a high probability. However all had been selected, on clinical grounds, to have a high enough suspicion of CAD to merit consideration for coronary angiography anyway, and indeed all went on to have this test.

Overall, the prevalence of a significant stenosis (taken as a ≥ 50% lesion) was 56%. Out of the 291 patients, 72 patients had a calcium score or zero and of these, 14 (19%) had at least 1 ≥ 50% coronary stenosis and 9 (13%) actually went on to have revascularisation.

Based on these results, the authors calculated a sensitivity of a zero calcium score to predict the absence of ≥ 50% coronary stenosis as only 45%, with a negative predictive valve of 68%, specificity of 91% and positive predictive valve of 81%. They also noted from their results that among the patients with a calcium score of 0 (72 in total), 8 patients had a low pre-test probability of CAD and indeed none of these 8 had a significant stenosis on angiography, as opposed to 12 (57%) of the 57 patients with an intermediate probability and 2 (29%) of the 7 patients with a high probability. However, a low CAD probability itself did not rule out significant stenosis, as out of the 291 patients studied, 14 had a low pre-test probability (though still enough clinical grounds to warrant angiography) but 4 (29%) of these actually had obstructive coronary artery disease.

This led the authors to conclude that CS should not be used as a gatekeeper for angiographic studies, at least in that population in which a clinical indication for coronary angiography already exists. They also pointed out that their data are particularly important in light of the current Expert Consensus Document endorsed by the ACC and the AHA [the current American Guidelines on the use of CS in CAD7]. Based on our findings, this strategy would lead to a high percentage of patients with a missed diagnosis of obstructive CAD in a group of patients with high enough clinical suspicion for CAD to assure an indication for invasive coronary angiography.2

The accompanying editorial by Dr. Rita Redberg in the same issue of JACC went on to discuss why the data from it were so different from those previously published,12, 13 which have shown that patients without coronary calcification are highly unlikely to have CAD and do not need further testing, with negative predictive values of 93% and positive predictive values of 68%. One explanation offered was of different characteristics in the 2 populations studied; another that CS and coronary angiography measure different stages of the atherosclerotic process (a point I will return to later). Another explanation, which was only briefly mentioned in the editorial but is actually of utmost importance, was differences in pre-test probability of disease. All in all, the usefulness of CS in the assessment of CAD was put into doubt.

Following the publication of this study and the accompanying editorial back in February this year, 5 letters to the editor have since been published regarding its findings in the August 10th, 2010 issue of JACC.14-19 Some of these are critical of the study, pointing out that numerous, and much larger, studies over the past 25 years have had results that are strikingly different14, 15 to their findings, suggesting that the current studys design, equipment or methodology or the fact that they excluded those with calcium scores >600 (which were analysed separately) were to blame for the discrepancy. One letter suggests that the way in which they have calculated sensitivity, specific, negative predictive value and positive predictive value are in error.14

However a few of these letters defended the study and questioned the editorial, which it was felt makes much broader conclusions about the utility of CS,17 bringing to attention the important point that is crucial to the whole debate: that the pre-test probability of CAD in the population under study is critical. One of the letters16 points out that meta-analysis12 that yield sensitivity estimates >90% have been used to recommend CS as a useful rule-out in patients, but only in those with a low pre-test probability. Gottleib et al. also point this out themselves in a reply:19 that their study focuses on only symptomatic patients and more so, those who have already been selected on clinical ground to warrant invasive coronary angiography (either because of symptoms, risk factors or both), which therefore makes their pre-test probability of CAD high, where as the vast majority of literature published on CS in CAD refers to asymptomatic individuals and those with a low or intermediate pre-test probability. The majority of patients (95%) in this study had either an intermediate or high pre-test probability. Thus they agree that to generalise their findings to all subgroups would be a grave mistake and point out that they have never done this, concluding that Searching for surrogate evidence of stenosis, as is the casewith CS, makes the performance of the test rely heavily on theprevalence of obstructive CAD and other biological factors inthe population it is being applied to, rendering CS unsuitablefor ruling out obstructive CAD in symptomatic patients.

So given the new NICE guidance in this country, what should our approach be? Would this cause significant disease to be missed? This guidance essentially states that CS should be used as a gate-keeper to further evaluation, but only in those with a low pre-test probability of CAD (10-29%, based on a method adapted from prior et al).21 It is of note that these patients may well have typical symptoms of angina. If the calcium score is 0 in this low-probability group, NICE state that nothing further needs to be done and causes of the chest pain other than CAD should be sought; if the score is between 1 and 400, NICE recommend a functional test; and if it is >400, they recommend that invasive coronary angiography be offered to the patient. Given the discussions above, it would seem that this is a reasonable approach, especially if a CS of zero prevents people from undergoing further unnecessary investigations and thus reduces potential patient anxiety and demand for resources within the NHS.

However calcium is a marker of disease relatively late in the pathway of atherosclerosis, which has also been pointed out by Gottlieb et al. through a fact demonstrated from their study which was that not only can significant atherosclerosis be present in the absence of CT-detectable calcification, but that 20% of the total number of completely occluded vessels analysed after angiography (13 out of 64) had no calcium detectable either. This may reflect previous findings8 and the current biological understanding of coronary plaques in which calcification is thought to happen downstream from formed atheroma (type IV lesions), in fibroatheromatous (type V) lesions as part of the healing process of usually subclinical plaque rupture events.9-11 However what is important to realise is that type IV lesions themselves can become unstable, rupture and occlude, leading to significant acute coronary events but before any calcification is present.

Therefore it is possible that based on CS alone, even in low-probability groups some significant coronary artery disease will be missed, albeit an extremely small percentage. As mentioned already, this was borne out in Gottlieb et. als study, where 4 out of 14 patients (29%) who had a low pre-test probability had obstructive coronary artery disease (although it is important to note that they were symptomatic). To highlight this fact, in our current audit of 50 patients sent for CS at St. Georges Hospital, 1 young female patient aged 33 deemed to have a pre-test probability of CAD of 10-29% (i.e. low) had a calcium score of 0, but went on to have angiography which showed a significant 80% proximal LAD lesion on angiography; angiography was performed because of her symptoms and family history of early onset CAD, the latter risk factor not being incorporated into the method of determining pre-test probability that NICE recommend. This highlights the importance of individualisation of treatment by the clinician based on all risk factors and clinical experience.

So where does this leave us? To conclude and defend her stance against the usefulness of CS, Dr. Redberg points out that ...none of the letters address the key clinical pointof whether an imaging test such as coronary artery calcium willgive us new information that leads to better patient care andimproved outcomes. Despite the use of CACS [coronary artery calcium scoring] for the last 20 years,there are still no data for either the asymptomatic or symptomaticgroup to show that this information benefits our patients..... Beforesubjecting healthy men and women to a test with significantradiation2 to 7 mSv or 100 chest roentgenogramsonemust be able to tell patients that there is a benefit from havingthis test. With no known benefit, CACS fails this essentialcriteria, and the harm, including cancer risk from radiation,and incidental findings prevail.20

8. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol 1995;15:151231.